title: Significance of matrix metalloproteinase-9 inhibition by imidapril for prevention of abdominal aortic aneurysms in angiotensin II type 1 receptor-knockout mice.
abstract: To clarify the matrix metalloproteinase (MMP)-9 inhibitory effect of an angiotensin-converting enzyme (ACE) inhibitor in vivo, we evaluated the effect of an ACE inhibitor against elastase-induced abdominal aortic aneurysm (AAA) progression in mice. Molecular models showed that imidapril bound directly to the mouse MMP-9 active center. An active form of imidapril, imidaprilat, dose-dependently inhibited MMP-9 activity in the extract from elastase-induced AAA in wild-type mice. Imidapril (10 mg/kg per day) was administered to wild-type or angiotensin II type 1 (AT1) receptor knockout mice. Blood pressure was significantly lower in AT1 receptor-knockout mice than in wild-type mice, but imidapril did not affect blood pressure in AT1 receptor-knockout mice. The aortic diameter was significantly expanded after elastase application, but the expansion was significantly lower in AT1 receptor-knockout mice than in wild-type mice. In AT1 receptor-knockout mice, the aortic expansion was further attenuated by imidapril. MMP-9 activity in aorta was significantly augmented after elastase application. The MMP-9 activity was significantly lower in AT1 receptor-knockout mice than in wild-type mice, and it was further attenuated by imidapril. In conclusion, MMP-9 inhibition by imidapril might contribute to the attenuation of AAA progression in AT1 receptor-knockout mice.
authors.affiliation: Department of Pharmacology, Osaka Medical College, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Zhong-Lian
authors.initials: ZL
authors.lastname: Li
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.forename: Mizuo
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D055786:Gene Knockout Techniques; D048289:Imidazolidines / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010196:Pancreatic Elastase / Q000009:adverse effects; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D014463:Ultrasonography
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; D061965:Matrix Metalloproteinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; C065166:imidapril; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C078006:imidaprilat